nt did not have meaningful effects on the pharmacokinetics of cabazitaxel. No data are available for patients with severe renal impairment or end-stage renal disease [see Use in Special Populations (8.6)].
Hepatic Impairment
No formal trials in patients with hepatic impairment have been conducted. As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations [see Warnings and Precautions (5.6), and Use in Special Populations (8.7)].
Drug interactions
As cabazitaxel is mainly metabolized by CYP3A in vitro, strong CYP3A inducers or inhibitors are expected to affect the pharmacokinetics of cabazitaxel.
Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
In vitro, cabazitaxel did not inhibit the multidrug-resistance protein 1 (MRP1) or 2 (MRP2). In vitro cabazitaxel inhibited the transport of P-gp and BRCP, at concentrations at least 38 fold what is observed in clinical settings. Therefore, the in vivo risk of cabazitaxel to inhibit MRPs, P-gp, or BCRP is unlikely at the dose of 25 mg/m.
In vitro, cabazitaxel is a substrate of P-gp, but not a substrate of MRP1, MRP2, or BCRP.
Long-term animal studies have not been performed to eva luate the carcinogenic potential of cabazitaxel.
Cabazitaxel was positive for clastogenesis in the in vivo micronucleus test, inducing an increase of micronuclei in rats at doses ≥ 0.5 mg/kg. Cabazitaxel increased numerical aberrations with or without metabolic activation in an in vitro test in human lymphocytes though no induction of structural aberrations was observed. Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames) test. The positive in vivo genotoxicity findings are consistent with the pharmacological activity of the compound (inhibition of tubulin depolymerization).
Cabazitaxel may impair fertility in humans. In a fertility study performed in female rats at cabazitaxel doses of 0.05, 0.1, or 0.2 mg/kg/day there was no effect of administration of the drug on mating behavior or the ability to become pregnant. There was an increase in pre-implantation loss at the 0.2 mg/kg/day dose and an increase in early resorptions at doses ≥ 0.1 mg/kg/day (approximately 0.02–0.06 times the human clinical exposure based on Cmax). In multi-cycle studies following the clinically recommended dosing schedule, atrophy of the uterus was observed at the 5 mg/kg dose level (approximately the AUC in patients with cancer at the recommended human dose) along with necrosis of the corpora lutea at doses ≥ 1 mg/kg (approximately 0.2 times the AUC at the clinically recommended human dose).
Cabazitaxel did not affect mating performances or fertility of treated male rats at doses of 0.05, 0.1, or 0.2 mg/kg/day. In multiple-cycle studies following the clinically recommended dosing schedule, however, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats treated intravenously with cabazitaxel at a dose of 1 mg/kg (approximately 0.2–0.35 times the AUC in patients with cancer at the recommended human dose), and minimal testicular degeneration (minimal epithelial single cell necrosis in epididymis) was observed in dogs treated with a dose of 0.5 mg/kg (approximately one-tenth of the AUC in patients with cancer at the recommended human dose).
The efficacy and safety of JEVTANA in combination with pr
